Systemic Administration of a Novel Immune-Stimulatory Pseudovirion Suppresses Lung Metastatic Melanoma by Regionally Enhancing IFN-γ Production

• Published in: Clinical cancer research Vol. 19; no. 3; pp. 668 - 679
• Main Authors: SAGA, Kotaro, TAMAI, Katsuto, YAMAZAKI, Takehiko, KANEDA, Yasufumi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2013
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line; Cricetinae; Dermatology; Disease Models, Animal; Female; Haplorhini; Immunoglobulin Fc Fragments - immunology; Injections, Intralesional; Interferon-gamma - biosynthesis; Interleukin-12 - immunology; Interleukin-12 - metabolism; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Medical sciences; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Mice; Pharmacology. Drug treatments; Sendai virus - immunology; Sendai virus - radiation effects; Tumors of the skin and soft tissue. Premalignant lesions; Viral Fusion Proteins - immunology; Virion - immunology; Virion - radiation effects; Immunostimulation; Lung; Malignant melanoma; Production; Advanced stage; Systemic route; Biosynthesis; Malignant tumor; Metastasis; Respiratory system; Cancer; Gamma interferon
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-1947

Cancer immunotherapy has encountered many difficulties in the face of the expectation to eradicate cancer, and new breakthroughs are required. We have previously shown that UV-inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) induce immunity against multiple tumor types. In this study, a novel pseudovirion that stimulates more robust antitumor immunity was designed for cancer treatment. First, we found that culturing murine splenocytes with HVJ-E in combination with interleukin (IL)-12 resulted in a remarkable increase in IFN-γ production compared with that observed in splenocytes cultured with IL-12 alone. The synergistic effects of HVJ-E and IL-12 on IFN-γ production were caused by viral F proteins independently of HVJ-E fusion activity and not by hemagglutination from hemagglutinin-neuraminidase (HN) proteins. We next constructed HN-depleted HVJ-E expressing the Fc region of immunoglobulin G (IgG) on the envelope and single-chain IL-12 containing the ZZ domain of protein A to produce an IL-12-conjugated HVJ-E particle without hemagglutinating activity. IL-12-conjugated HVJ-E dramatically enhanced the amount of IFN-γ produced by immune cells. Intratumoral injection of IL-12-conjugated HVJ-E eradicated murine melanomas more effectively than injection of wild-type HVJ-E through increased production of melanoma-specific CTLs. IL-12-conjugated HVJ-E preferentially accumulated in the lungs after systemic administration. When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12-conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-γ in the lungs and generating large numbers of melanoma-specific CTLs. IL-12-conjugated HVJ-E is a promising tool for the treatment of cancers, including lung metastasis.